chr16-23636095-G-A

Variant names:

• chr16-23636095-G-A
• rs587776407
• NM_024675.4:c.451C>T

Variant summary

Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_024675.4(PALB2):​c.451C>T​(p.Gln151*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 32)
• Consequence: PALB2 NM_024675.4 stop_gained
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:9
• Conservation: PhyloP100: 0.190
• Publications: 6 publications found

Genes affected

PALB2 (HGNC:26144): (partner and localizer of BRCA2) This gene encodes a protein that may function in tumor suppression. This protein binds to and colocalizes with the breast cancer 2 early onset protein (BRCA2) in nuclear foci and likely permits the stable intranuclear localization and accumulation of BRCA2. [provided by RefSeq, Jul 2008]

PALB2 Gene-Disease associations (from GenCC):

• hereditary breast carcinoma

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen, Ambry Genetics
• Fanconi anemia complementation group N

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae), ClinGen, Ambry Genetics
• pancreatic cancer, susceptibility to, 3

  Inheritance: AD Classification: STRONG Submitted by: Genomics England PanelApp, Labcorp Genetics (formerly Invitae)
• familial ovarian cancer

  Inheritance: AD Classification: MODERATE Submitted by: ClinGen
• Fanconi anemia

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• hereditary nonpolyposis colon cancer

  Inheritance: AD Classification: LIMITED Submitted by: ClinGen

ACMG classification

Our verdict: Pathogenic. The variant received 18 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 16-23636095-G-A is Pathogenic according to our data. Variant chr16-23636095-G-A is described in CliVar as Pathogenic. Clinvar id is 143977.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-23636095-G-A is described in CliVar as Pathogenic. Clinvar id is 143977.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-23636095-G-A is described in CliVar as Pathogenic. Clinvar id is 143977.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-23636095-G-A is described in CliVar as Pathogenic. Clinvar id is 143977.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-23636095-G-A is described in CliVar as Pathogenic. Clinvar id is 143977.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-23636095-G-A is described in CliVar as Pathogenic. Clinvar id is 143977.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-23636095-G-A is described in CliVar as Pathogenic. Clinvar id is 143977.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-23636095-G-A is described in CliVar as Pathogenic. Clinvar id is 143977.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-23636095-G-A is described in CliVar as Pathogenic. Clinvar id is 143977.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-23636095-G-A is described in CliVar as Pathogenic. Clinvar id is 143977.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-23636095-G-A is described in CliVar as Pathogenic. Clinvar id is 143977.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-23636095-G-A is described in CliVar as Pathogenic. Clinvar id is 143977.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-23636095-G-A is described in CliVar as Pathogenic. Clinvar id is 143977.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-23636095-G-A is described in CliVar as Pathogenic. Clinvar id is 143977.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-23636095-G-A is described in CliVar as Pathogenic. Clinvar id is 143977.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-23636095-G-A is described in CliVar as Pathogenic. Clinvar id is 143977.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-23636095-G-A is described in CliVar as Pathogenic. Clinvar id is 143977.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-23636095-G-A is described in CliVar as Pathogenic. Clinvar id is 143977.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-23636095-G-A is described in CliVar as Pathogenic. Clinvar id is 143977.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-23636095-G-A is described in CliVar as Pathogenic. Clinvar id is 143977.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-23636095-G-A is described in CliVar as Pathogenic. Clinvar id is 143977.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-23636095-G-A is described in CliVar as Pathogenic. Clinvar id is 143977.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PALB2	NM_024675.4	c.451C>T	p.Gln151*	stop_gained	Exon 4 of 13	ENST00000261584.9	NP_078951.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PALB2	ENST00000261584.9	c.451C>T	p.Gln151*	stop_gained	Exon 4 of 13	1	NM_024675.4	ENSP00000261584.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Familial cancer of breast Pathogenic:5

Mar 30, 2023

Myriad Genetics, Inc.

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered pathogenic. This variant creates a termination codon and is predicted to result in premature protein truncation. -

Nov 22, 2023

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change creates a premature translational stop signal (p.Gln151*) in the PALB2 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in PALB2 are known to be pathogenic (PMID: 17200668, 17200671, 17200672, 24136930, 25099575). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with breast cancer (PMID: 25099575). ClinVar contains an entry for this variant (Variation ID: 143977). For these reasons, this variant has been classified as Pathogenic. -

Apr 13, 2018

Counsyl

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

This submission and the accompanying classification are no longer maintained by the submitter. For more information on current observations and classification, please contact variantquestions@myriad.com. -

May 13, 2019

Leiden Open Variation Database

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: curation

Curators: Marc Tischkowitz, Arleen D. Auerbach. Submitter to LOVD: Marc Tischkowitz. -

not provided Pathogenic:2

-

SNPedia

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Nov 10, 2023

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of disease; Truncating variants in this gene are considered pathogenic by a well-established clinical consortium and/or database; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 28864920, 25099575, 28779002, 33471991, 17200668, 31300551, 17200671, 17200672, 24136930) -

Hereditary cancer-predisposing syndrome Pathogenic:1

Mar 20, 2025

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.Q151* pathogenic mutation (also known as c.451C>T), located in coding exon 4 of the PALB2 gene, results from a C to T substitution at nucleotide position 451. This changes the amino acid from a glutamine to a stop codon within coding exon 4. This mutation has been detected in multiple breast cancer patients (Antoniou AC et al. N Engl J Med, 2014 Aug;371:497-506; Decker B et al. J Med Genet, 2017 11;54:732-741; Ding YC et al. Fam Cancer, 2018 04;17:187-195; Fostira F et al. J Med Genet, 2020 01;57:53-61; Dorling et al. N Engl J Med. 2021 02;384:428-439). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation. -

Hereditary breast ovarian cancer syndrome Pathogenic:1

Apr 19, 2024

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: PALB2 c.451C>T (p.Gln151X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The variant was absent in 251360 control chromosomes (gnomAD). c.451C>T has been reported in the literature in individuals affected with breast cancer, ovarian cancer, prostate cancer and other cancers (Antoniou_2014, Yang_2019). These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 25099575, 31841383). ClinVar contains an entry for this variant (Variation ID: 143977). Based on the evidence outlined above, the variant was classified as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.60	D
BayesDel_noAF	Uncertain	0.0
CADD	Pathogenic	28
DANN	Uncertain	0.99
Eigen	Benign	0.087
Eigen_PC	Benign	-0.25
FATHMM_MKL	Benign	0.070	N
PhyloP100		0.19
Vest4		0.76
GERP RS		-0.17
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=0/200	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs587776407; hg19: chr16-23647416;